Chymase is stored as an ingredient in granules of mast cells (MC), which are one of the inflammatory cells closely related to inflammation, and is widely present mainly in the tissue such as skin, heart, vascular walls, intestines etc. (see Non-Patent Document 1). Human chymase is known as an enzyme for specifically producing angiotensin II (i.e., Ang II) from angiotensin I (i.e., Ang I) independently from angiotensin converting enzyme. There is a report that, in human cardiac tissue, 80% of the production of angiotensin II is derived from by chymase (see Non-Patent Document 2). Ang II is known to be closely related to regulation of the blood pressure, diuretic regulation, and hypertrophy and remodeling of the cardiovascular system, that is, the migration and proliferation of smooth muscle cells etc. and the growth of the extracellular matrix in the cardiovascular system tissue. From these findings, it is suggested that chymase is closely related to cardiovascular lesions through production of Ang II. In addition to production of Ang II, it is reported that chymase has the following actions based on its protease activity: 1) degradation of the extracellular matrix (see Non-Patent Document 3), activation of collagenase (see Non-Patent Document 4), and production of collagen (see Non-Patent Document 5); 2) processing and activation of inflammatory cytokine, for example, release of latent TGF β1 from extracellular matrix (see Non-Patent Document 6), activation of latent TGFβ1 to active TGFβ1 (see Non-Patent Document 7), and activation of IL-1β (see Non-Patent Document 8); 3) activation of stem cell factor (SCF) which induces differentiation and proliferation of MCs (see Non-Patent Document 9); 4) degradation of apolipoprotein B in LDL (see Non-Patent Document 10) and degradation of apolipoprotein A in HDL (see Non-Patent Document 11); and 5) conversion of big endothelin to a bioactive peptide comprised of 31 amino acid residues (ET(1-31)) (see Non-Patent Document 12). Further, it is reported that chymase stimulates rat peritoneal mast cells to induce degranulation (see Non-Patent Document 13) and that administration of human chymase intraperitoneally to mice or subcutaneously to guinea pigs induces infiltration of eosinophil and other leukocytes (see Non-Patent Document 14), and causes continuous increase of vascular permeability not through the action of histamine (see Non-Patent Document 15). These various reports relating to the action of chymase suggest that chymase plays an important role in the processes of tissue inflammation, repair, and healing, and in allergic conditions. It is believed that in these processes, the excessive reaction of chymase is involved in various diseases.
From the above-mentioned findings, a chymase inhibitor can be expected to be useful as a pharmaceutical for the prevention or treatment of for example, bronchial asthma, urticaria, atopic dermatitis, allergic conjunctivitis, rhinitis, rheumatoid arthritis, mastocytosis, scleroderma, heart failure, cardiac hypertrophy, congestive heart failure, hypertension, atherosclerosis, myocardial ischemia, myocardial infarction, restenosis after PTCA, restenosis after bypass graft surgery, ischemic peripheral circulatory disorders, hyperaldosteronism, diabetic retinopathy, diabetic nephropathy, nephritis, glomerulosclerosis, renal insufficiency, psoriasis, solid tumor, postoperative adhesion, glaucoma, and ocular hypertension, and other diseases.
On the other hand, small molecule chymase inhibitors are already shown in books (see Non-Patent Document 16) or review articles (see Non-Patent Documents 17, 18, and 19). The efficacy of several inhibitors among these in animal disease models has been reported (vascular lipid deposition: see Patent Document 1, heart failure: see Non-Patent Document 20, myocardial infarction: see Patent Document 2, see Non-Patent Document 21, see Non-Patent Document 22, aortic aneurysm: see Patent Document 3, restenosis: see Patent Document 4, atopic dermatitis: see Patent Document 5, pruritus: see Patent Document 6, eosinphilia: see Patent Document 7, fibrosis: see Patent Document 8). Further, recently, in addition to the chymase inhibitors described in the above-mentioned books and review articles, imidazolidinedione derivatives (see Patent Document 9), phosphonic acid derivatives (see Patent Document 10), benzothiophensulfonamide derivatives (see Patent Document 11), imidazole derivatives (see Patent Document 12), triazolidine derivatives (see Patent Document 13), pyridone derivatives (see Patent Document 14), thiazolimine and oxazolimine derivatives (see Patent Document 15), and enamide derivatives (see Patent Document 16) are disclosed as novel chymase inhibitors. However, there are no examples of the above chymase inhibitors being practically used as pharmaceuticals.
Further, 1,4-diazepan-2,5-dione skeleton compounds similar in structure to the present invention are disclosed in documents (see Non-Patent Documents 23 and 24) etc., but none has the electron withdrawing group such as a carbonyl group, sulfonyl group, or other electron withdrawing group at the 4-position nitrogen atom like in the present invention. Further, there is no disclosure at all of chymase inhibitory activity like in the present invention. Further, Patent Document 17 and Non-Patent Document 25 disclose a 1,4-benzodiazepine derivative as a 7-membered lactam derivative having a carbonyl group, sulfonyl group, or other electron withdrawing group at the 4-position nitrogen atom, but these derivatives differ in skeleton from the present invention. Further, there is no disclosure at all of chymase inhibitory activity like in the present invention.
Further, as examples of production of a non-fused 1,4-diazepan-2,5-dione derivative similar to the present invention, a 7-membered ring closure reaction using lactamization etc. are reported in Non-Patent Documents 26 and 27. However, up to now, there has been no report of a production method characterized by introducing an electron withdrawing group at the 4-position nitrogen atom of a 1,4-diazepan-2,5-dione derivative, like in the present invention. Further, there has been no report up to now of a production method of 1,4-diazepan-2,5-dione derivative characterized by an intramolecular alkylation reaction at the portions corresponding to the 4-position nitrogen atom and 3-position carbon atom, like in the present invention.
[Patent Document 1] WO01-32214
[Patent Document 2] WO03-07964
[Patent Document 3] WO03-07964
[Patent Document 4] WO02-32881
[Patent Document 5] WO01-62294
[Patent Document 6] WO00-51640
[Patent Document 7] WO00-162293
[Patent Document 8] WO00-162292
[Patent Document 9] WO02-83649
[Patent Document 10] WO03-35654
[Patent Document 11] WO03-78419
[Patent Document 12] WO04-07464
[Patent Document 13] Japanese Patent Publication (A) No. 2003-342265
[Patent Document 14] Japanese Patent Publication (A) No. 2004-67584
[Patent Document 15] WO05-000825
[Patent Document 16] WO05-073214
[Patent Document 17] DE 2257171
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